a study to evaluate the safety and tolerability of tos-358 in adults with select solid tumors

Conditions: Squamous Cell Carcinoma of Head and Neck; Urothelial Carcinoma; Endometrial Cancer; HR+/HER2-negative Breast Cancer

Summary: the goal of this clinical trial is to evaluate the safety of tos-358 in adults with select solid tumors who meet study enrollment criteria. the main questions it aims to answer are: 1. what is the maximum tolerated dose and recommended dose for phase 2? 2. how safe and tolerable is tos-358 at different dose levels when taken orally once or twice per day?

this study will be conducted in two parts: a dose finding portion to determine the maximum tolerated dose and recommended phase 2 dose (rp2d) of tos-358 administered orally on once a day (qd) and twice daily (bid) schedules, and a dose expansion portion to evaluate safety and tolerability in tumor-specific cohorts administered tos-358 at the recommended phase 2 dose and schedule. adult subjects with histologically confirmed diagnosis of hormone receptor-positive (hr+), human epidermal growth factor receptor 2 (her2) negative breast cancer, squamous cell carcinoma of the head and neck, urothelial cancer, or endometrial cancer with known pik3ca mutations or amplifications (as determined at a college of american pathologists/clinical laboratory improvement amendments \[cap/clia\]-certified or equivalently accredited diagnostic laboratory using a validated test), who meet all of the eligibility criteria will be enrolled in the phase 1 portion of the study. in the dose finding portion of the study, tos-358 will be evaluated as a single-agent at multiple dose levels administered orally until disease progression, unacceptable toxicity, or until meeting any other reason for discontinuation as specified in the protocol.

Eligibility criteria:
key inclusion criteria * locally advanced, recurrent, or metastatic, incurable (any number of previous lines of therapy is allowed), histologically or cytologically confirmed; hr +/her2- breast cancer; squamous cell carcinoma of the head and neck; urothelial cancer; or endometrial cancer * willing and able to provide written informed consent for this study * adults ≥ 18 years old at time of consent * known pik3ca mutations or amplifications as determined at a cap/clia-certified or equivalently accredited diagnostic laboratory using a validated test * measurable disease by recist 1.1 * eastern cooperative oncology group (ecog) performance status of 0 or 1 * life expectancy ≥ 3 months, as determined by the investigator * adequate bone marrow, liver, and kidney function within 14 days prior to first dose of investigational product * fasting plasma glucose \< 126 mg/dl and hemoglobin a1c (hba1c) \< 6.5% * available archived or fresh tumor tissue sample for detection of pik3ca mutation by central laboratory test key exclusion criteria * recent systemic anticancer treatment prior to start of treatment (exception: patients with breast cancer who were receiving a fulvestrant-containing regimen at the time of informed consent may remain on fulvestrant while receiving study treatment) * prior treatment with any pi3k, akt, or mtor inhibitor, or any agent whose mechanism of action is to inhibit the pi3k-akt-mtor pathway, except for patients with breast cancer * second malignancy (solid or hematologic) within the past 3 years except: adequately treated basal cell or squamous cell skin cancer; carcinoma in situ of the cervix, or prostate cancer with gleason score \< 6 and undetectable prostate specific antigen over 12 months; ductal breast carcinoma in situ with full surgical resection (ie, negative margins); treated medullary or papillary thyroid cancer; metaplastic breast cancer * history of diabetes of any type * cushing syndrome * congestive heart failure (new york heart association class iii to iv), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within 6 months prior to the first dose of investigational product * known active central nervous system (cns) metastases.